INHIBITION OF TRANSPLANT ARTERIOSCLEROSIS IN RAT AORTIC GRAFTS BY LOW MOLECULAR WEIGHT HEPARIN DERIVATIVES

Abstract

The effects of low molecular weight heparin derivatives with a low anticoagulant activity on transplant arteriosclerosis (TA) in a rat aortic transplant model were investigated. TA was induced by ischemia in the syngeneic transplants and primarily by immunological mechanisms in the allogeneic transplants. Treatment with the heparin derivatives, OAM 71262 or LA-heparin, was administered in a dosage of 250 micrograms/kg/hr by mini-osmotic pumps during 8 weeks. No immunosuppressive regimen was given to the recipient rats in either model. All rats were killed 8 weeks after aortic grafting. The grafts were examined for intimal and medial changes using an image analysis system. Heparin derivatives had a beneficial effect on both the intimal thickening and the medial injury in the syngeneic transplants, but not in the allogeneic grafts. In the syngeneic LA-heparin treated grafts, the thickness of the intima was less than that in the syngeneic control grafts (P < 0.05). In the syngeneic transplants, a significant increase was observed in the media after treatment with OAM 71262 (P < 0.01) as well as those with LA-heparin (P < 0.001). In the syngeneic grafts treated with both heparin derivatives, a significant reduction in the antigen expression of alpha-actin-containing smooth muscle cells in the intima, transforming growth factor-beta 1 both in the media and adventitia, and platelet-derived growth factor-beta receptors in the adventitia was observed immunohistochemically. In summary, low molecular weight heparin derivatives with low anticoagulant activity partially inhibited ischemia-induced syngeneic TA, whereas no such effect could be demonstrated in nonimmunosuppressed recipients with allogeneic grafts.